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Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2 years of treatment with ivacaftor in a real-world setting
JCF-01511; No of Pages 7
Journal of Cystic Fibrosis xx (2017) xxx – xxx www.elsevier.com/locate/jcf
Original Article
Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2 years of treatment with ivacaftor in a real-world setting Dominique Hubert a,b,⁎, Clémence Dehillotte c , Anne Munck d , Valérie David e , Jinmi Baek f , Laurent Mely g , Stéphane Dominique h , Sophie Ramel i , Isabelle Danner Boucher j , Sylvaine Lefeuvre k , Quitterie Reynaud l , Virginie Colomb-Jung c , Prissile Bakouboula f , Lydie Lemonnier c a
h
Pulmonary Department, Adult CF Centre, Cochin Hospital, AP-HP, Paris, France b Université Paris Descartes, Sorbonne Paris Cité, Paris, France c Vaincre la Mucoviscidose, Paris, France d Pediatric CF Centre, Robert Debré Hospital, AP-HP, Paris, France e Pediatric CF Centre, Hôpital Mère-Enfant, Nantes, France f Clinical Research Unit, Cochin Hospital, AP-HP, Paris, France g CF Centre, Renée Sabran Hospital, Giens, France Pulmonary Department, Adult CF Centre, Charles Nicolle Hospital, Rouen University Hospital, Rouen, France i CF Centre, Centre héliomarin de Perharidy, Roscoff, France j Pulmonary Department, Adult CF Centre, Laennec Hospital, Nantes, France k Paediatric CF Centre, Hôpital Sud, Rennes, France l Adult CF Centre Lyon Sud, Hospices Civils de Lyon, Lyon, France Received 3 April 2017; revised 3 July 2017; accepted 3 July 2017 Available online xxxx
Abstract Background: Ivacaftor has been shown to improve lung function and body weight in patients with CF and a gating mutation. Real-world evaluation is warranted to examine its safety and effectiveness over the long term. Methods: A retrospective observational multicentre study collected clinical data in the year before and the 2 years after ivacaftor initiation in patients with CF and a Gly551Asp-CFTR mutation. Results: Fifty-seven patients were included. Mean absolute change in FEV1% predicted improved from baseline to Year 1 (8.4%; p b 0.001) and Year 2 (7.2%; p = 0.006). Statistically significant benefits were observed with increased body mass index, fewer Pseudomonas aeruginosa and Staphylococcus aureus positive cultures, and decreased IV antibiotics and maintenance treatment prescriptions (including azithromycin, Dornase alpha and nutritional supplements). No significant adverse events were reported. Conclusion: The clinical benefits of ivacaftor reported in previous clinical trials were confirmed in a real-world setting two years post-initiation, also reducing treatment burden. © 2017 Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. Keywords: Cystic fibrosis; CFTR modulators; Lumacaftor
⁎ Corresponding author at: Pulmonary Department, Adult CF Centre, Cochin Hospital, AP-HP, Paris, France. E-mail address: [email protected] (D. Hubert).
http://dx.doi.org/10.1016/j.jcf.2017.07.001 1569-1993/© 2017 Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. Please cite this article as: Hubert D, et al, Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2..., J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.07.001
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D. Hubert et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
1. Introduction Ivacaftor is an oral cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that improves chloride transport in cells expressing certain CFTR gating mutations. In clinical trials lasting up to 144 weeks, ivacaftor was shown to improve lung function, body weight, and sweat chloride in patients with cystic fibrosis (CF) and a Gly551Asp-CFTR mutation [1–3]. Ivacaftor was approved by the Food and Drug Administration and by the European Medicines Agency in 2012 for the treatment of CF patients over the age of six with a Gly551Asp-CFTR mutation. It has been available in France since April 2012 for these patients, regardless of their respiratory function level. Ivacaftor was subsequently shown to be effective in carriers of other CFTR gating mutations [4] (available in France from May 2015) and in children aged 2 to 5 with CF and a CFTR gating mutation [5] (available from February 2017). The benefits of ivacaftor reported in clinical trials were evident, and studies from the US Registry suggested that improvements in respiratory function and nutritional status were maintained after 3 years of treatment [6]. To confirm these results and to provide additional information on other aspects of the disease, such as changes in bacterial lung colonisation and treatment needs, we designed a “real-world study” in the French population. The objective of our study was to evaluate the clinical response to ivacaftor in French CF patients aged 6 or older with a Gly551Asp-CFTR mutation after 1 and 2 years of treatment in a real-world setting. 2. Methods A multicentre retrospective observational study was conducted on patients with CF and at least one Gly551Asp-CFTR mutation who had initiated treatment with ivacaftor before 1st June 2013. Ivacaftor treatment reporting in the French CF Registry began in 2013, therefore eligible patients had to be recruited through their CF Centre. Each of the 45 French CF centres were contacted and asked if they had patients who had been treated with ivacaftor before 1st June 2013; 25 confirmed they did and agreed to participate, and 57 patients were included. No information was collected about eligible patients with Gly551Asp-CFTR who were not taking ivacaftor. Demographic and clinical data were collected by a clinical research assistant from patient files for the year prior to and the year after ivacaftor was initiated. When available, clinical data collection was extended to the second year of ivacaftor treatment; this applied to the subjects for whom treatment had been initiated before 30th September 2012 as data collection stopped on 30th September 2014. All the patients who had been included in the initial phase 3 ivacaftor clinical trials were also included in this study; the date of initiation was determined after their placebo/treatment group allocation was revealed. The primary endpoint under consideration in our analysis was the absolute change in forced expiratory volume in one
second (FEV1) from baseline (last value before ivacaftor initiation) to 12 months after treatment initiation. FEV1 data was collected in litres and expressed as percentage of the predicted value according to Knudson's reference. Secondary endpoints were the absolute change from baseline to 24 months in percent predicted FEV1, and changes from baseline to 12 and 24 months after ivacaftor initiation in the following parameters: weight and BMI z score, bacteria isolated in sputum (Pseudomonas aeruginosa and Staphylococcus aureus), number (and number of days) of IV and oral antibiotic courses, number of outpatient visits and number of hospitalisations, and of concomitant treatments. Sweat chloride was measured before and after ivacaftor initiation. We also looked for a change in pancreatic insufficiency and diabetes mellitus status. When available, we collected results of bone mass density measured by dual energy X-ray absorptiometry (DEXA) at the L2–L4 lumbar spine and at the femoral neck at baseline and after at least one year of ivacaftor treatment. Other data collected included age at treatment initiation, gender, CFTR genotype, date of treatment initiation, any interruption or discontinuation of ivacaftor. All data were retrieved from the French CF Registry. Adverse events, excluding pulmonary exacerbations, were collected retrospectively from patient files. The database collected for this study was added to the French Registry after it had been completed. Safety and tolerance evaluation was based on the adverse events observed during the two-year follow-up. Clinical laboratory values (haematology, C-Reactive Protein, liver enzymes, HbA1c) were collected before ivacaftor initiation and at 12 and 24 months. The study was approved by our Institutional Review Board (file # 13.652). All subjects received written information and provided verbal informed consent; following French regulations regarding observational studies, no signed agreement was requested. This study is registered with Clinical Trials.gov., number NCT02194881. 2.1. Statistical analysis Quantitative variables are expressed as means and standard deviations. Medians and ranges are used as appropriate. Descriptive data are expressed as proportions (%) of patients for whom data were available. Year 1 and Year 2 data were compared with baseline values using paired Student's t-tests and non-parametric Wilcoxon tests for continuous data and McNemar's tests for categorical data. All analyses were performed using SAS 9.4 (SAS Institute, Cary, NC). Two-sided p-values b 0.05 were considered statistically significant. The statistical analysis is limited by multiple comparisons, which was not adjusted for. 3. Results 3.1. Subjects The study population consisted of 57 patients with CF, including 30 children and adolescents and 27 adults (47%),
Please cite this article as: Hubert D, et al, Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2..., J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.07.001
D. Hubert et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
with a mean age (± SD) of 21.5 (± 13.1) years. Their clinical characteristics at ivacaftor initiation are shown in Table 1. Six of them had previously participated in the initial phase 3 clinical trials. Nine had severe respiratory function (FEV1 b 40%). At Year 1, the study included fifty-six subjects as treatment had been discontinued in one patient. At Year 2, 48 subjects were still included; one had discontinued ivacaftor treatment and 7 patients had not reached a two-year treatment duration. 3.2. Respiratory function (Table 2) There was a statistically significant increase in FEV1 in the entire cohort, with an absolute change in FEV1 of 8.4% at Year 1 (p b 0.001) and of 7.2% at Year 2 (p = 0.006) in comparison to FEV1 prior to ivacaftor initiation. The highest response was seen in the adolescent age group. The increase was not statistically significant in 6–12 year olds at both time points or at Year 2 in adults. The 9 patients with severe respiratory function had an absolute increase in FEV1 of 5% at Year 1 and of 4.8% at Year 2 compared to baseline, but this result was not statistically significant. 3.3. Other clinical parameters There were statistically significant increases in weight and in BMI z score in the whole cohort as well as in BMI in adults at Year 1 and Year 2 (Table 3). There was no change in the mean numbers of outpatient visits and of sputum sample analyses during Year 1 compared to the year prior to ivacaftor initiation though they were lower during Year 2 (Table 3). Pulmonary bacterial colonisation with Pseudomonas aeruginosa and Staphylococcus aureus decreased after one year of treatment, and remained low after 2 years (Table 3).
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Table 2 Absolute change in per cent predicted FEV1 at Year 1 and Year 2 after ivacaftor treatment initiation in comparison to baseline. Year 1 n All subjects
56
Year 2
Mean p Value change ± SD 8.4 ± 14.3
n
Mean p Value change ± SD
0.0001 44
7.2 ± 15.5
0.006
Subjects by age distribution 6–12 years 16 7.3 ± 19.0 ≥12–18 years 14 12.5 ± 11.5 ≥18 years 26 7.0 ± 12.5
NS 0.004 0.009
11 11 22
6.1 ± 18.4 12.3 ± 6.1 5.5 ± 13.9
NS 0.053 NS
Subjects by respiratory severity FEV1 ≥ 40% pred. 49 9.1 ± 15.3 FEV1 b 40% pred. 7 5.0 ± 8.8
0.0004 38 0.126 6
7.8 ± 17.2 4.8 ± 6.8
0.017 0.069
n: number of patients - NS: not significant.
In comparison to the year prior to ivacaftor initiation, the number of IV antibiotic courses (and days) decreased significantly over the first and second years and a trend towards a decrease in the oral antibiotic intake appeared over the second year (Table 3). No change in the number of hospitalisations was observed, which was very low in all periods (Table 3). The rates of pancreatic insufficiency and of cystic fibrosis related diabetes (CFRD) remained constant. HbA1c did not change significantly during the study (6.0 ± 0.9% at baseline, 5.8 ± 0.7% at Year 1 and 5.8 ± 0.6% at Year 2). Data on bone mass density were available for 22 patients and showed no apparent change: 12 patients had lumbar spine measurement (Z-score − 0.8 before and − 0.9 after ivacaftor) and 10 patients had femoral neck measurements (Z-score − 0.9 before and − 1.0 after ivacaftor).
Table 1 Baseline patient characteristics. Population
All (n = 57)
Children (6–12 yrs) (n = 16)
Adolescents (≥ 12–18 yrs) (n = 14)
Adults (N 18 yrs) (n = 27)
17.6 (6.1–51.8)
8.2 (6.1–11.8)
14.2 (12.1–17.7)
31.3 (18.9–51.8)
Sex Male, n (%) Female, n (%) Age at diagnosis in years, median (range)
34 (59.6) 23 (40.4) 0.5 (0–37.3)
8 (50) 8 (50) 0.1 (0–0.3)
8 (57.1) 6 (42.9) 0.9 (0–15.7)
18 (66.7) 9 (33.3) 3.0 (0–37.3)
CFTR genotype, n (%) G551D/F508del Severe genotype Mild genotype Pancreatic insufficiency, n (%) Diabetes, n (%) Weight, kg (mean ± SD) FEV1,% predicted (mean ± SD) FEV1 b 40%, n (%)
34 (59.6) 48 (84.2) 9 (15.8) 47 (82.5%) 7 (12.3%) 48.2 ± 17.6 72.3 ± 26.4 9 (15.8)
12 (75) 15 (93.8) 1 (6.3) 14 (87.5) 0 25.9 ± 6.7 84.3 ± 12.7 0
8 (57.1) 13 (92.9) 1 (7.1) 11 (84.6) 0 49.5 ± 13.1 86.0 ± 24.4 1 (8.3)
14 (51.9) 20 (74.1) 7 (25.9) 22 (81.5) 7 (26.9) 61.4 ± 7.4 59.5 ± 27.2 8 (30.8)
Bacterial respiratory colonisation, n (%) Pseudomonas aeruginosa Staphylococcus aureus Sweat chloride, mmol/L (mean ± SD)
32 (58.2) 42 (75.0) 100.6 ± 29.3
4 (26.7) 13 (86.7) 111.9 ± 30.3
8 (61.5) 10 (71.4) 91.7 ± 24.5
20 (74.1) 19 (70.4) 99.0 ± 30.1
Age in years, median (range)
Please cite this article as: Hubert D, et al, Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2..., J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.07.001
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Table 3 Evolution of other clinical parameters after one and 2 years of ivacaftor treatment in comparison to baseline. Baseline
Weight (kg) BMI z-score BMI in adults (kg/m2) Number of outpatient visits/year Number of sputum sample analyses/year Pseudomonas aeruginosa Staphylococcus aureus Number of IV antibiotic courses/year Number of days of IV antibiotic courses/year Number of oral antibiotic courses/year Number of days of oral antibiotic courses/year Number of hospitalisations/year Number of days of hospitalisation/year
Year 1
Year 2
n
Mean ± SD or proportion of patients (%)
n
Mean ± SD or proportion of patients (%)
p Value
n
Mean ± SD or proportion of patients (%)
p Value
54 54 26 57 52 52 52 57 57 57 57 57 57
48.2 ± 17.6 0 ± 0.9 21.2 ± 1.5 6.0 ± 3.7 5.0 ± 2.7 58.2 75.0 0.9 ± 1.3 12.7 ± 21.0 1.8 ± 2.1 37.2 ± 58.0 0.4 ± 1.0 2.4 ± 8.0
55 55 25 56 52 52 52 56 56 56 56 56 56
52.3 ± 17.5 0.3 ± 1.0 22.1 ± 1.9 5.8 ± 2.9 4.3 ± 1.7 33.3 57.4 0.3 ± 0.9 5.6 ± 15.3 1.1 ± 1.6 23.4 ± 52.9 0.2 ± 0.7 1.2 ± 5.2
b0.0001 b0.0001 0.0004 NS NS 0.0005 0.004 0.008 0.013 0.120 0.118 NS NS
45 45 19 48 47 47 47 48 48 48 48 48 48
53.8 ± 16.9 0.4 ± 1.1 22.7 ± 2.7 4.9 ± 3.0 3.4 ± 1.9 41.3 58.7 0.3 ± 0.8 5.4 ± 14.7 1.1 ± 1.6 23.6 ± 57.7 0.3 ± 1.0 2.2 ± 7.6
b0.0001 b0.0001 0.003 0.038 0.001 0.039 0.022 0.011 0.016 0.072 0.055 NS NS
n: number of patients - NS: not significant.
3.4. CFTR function Sweat chloride levels decreased significantly with ivacaftor treatment with a mean (± SD) of 100.6 (± 29.3) mmol/L before and 40.1 (± 24.7) mmol/L after initiation (p b 0.001). 3.5. Maintenance treatment (Table 4) The number of azithromycin prescriptions decreased over the first and the second years of ivacaftor therapy. Dornase alfa prescriptions and oral supplements decreased only during the second year of ivacaftor treatment. Hypertonic saline was less frequently prescribed after ivacaftor initiation, but the result was not statistically significant as the number of patients involved was much lower. There was a trend for less frequent inhaled bronchodilators and corticosteroids in the second year of ivacaftor treatment. No change was observed for inhaled antibiotics or pancreatic enzymes. 3.6. Safety and adverse events Excluding pulmonary exacerbations, a total of 34 adverse events were reported in 21 patients. Some occurred soon after
ivacaftor initiation and disappeared within a few days: fever, rhino-pharyngitis, nausea, abdominal pain and impaired intestinal motility, headache, myalgia, fatigue and orchitis. Adverse events that lasted more than a month included abdominal pain and vomiting, rash or eczema, chest pain, atrial fibrillation, depression, arthritis, asthma, breast hypertrophy and headache. Liver abnormalities were reported in 3 patients. No deaths or lung transplantations occurred in the first 2 years of ivacaftor treatment. Ivacaftor was discontinued in two patients at 24 and 53 weeks of treatment, due to increased liver enzyme levels and diagnosis of liver cirrhosis, respectively. There were 12 interruptions of ivacaftor in 10 patients, after a mean treatment duration of 261 days (range: 7–589 days) and with a mean duration of 60 days (range: 1–220 days). These interruptions were motivated by clinical signs including hepatitis, rash, rhino-pharyngitis, abdominal pain, vomiting, headache and severe depression or were the result of poor compliance (in 3 patients). Overall, no increase in hepatic transaminase levels was observed. Red cell counts remained stable and a significant decrease in white blood cell and platelet counts was noted (Table 5). These changes are not likely clinically meaningful.
Table 4 Changes in maintenance treatment after 1 and 2 years of ivacaftor treatment in comparison to baseline. Baseline
Azithromycin Dornase alfa Hypertonic saline Inhaled antibiotics Inhaled bronchodilators Inhaled corticosteroids Pancreatic enzymes Oral supplements
Year 1
Year 2
n
Proportion of patients (%)
n
Proportion of patients (%)
p Value
n
Proportion of patients (%)
p Value
55 57 56 55 57 56 56 53
47.4 56.1 15.8 59.6 80.7 63.2 89.5 28.1
55 55 55 55 53 55 55 53
35.7 50.0 8.9 57.1 69.6 58.9 91.1 23.2
0.039 NS NS NS NS NS NS NS
46 46 46 46 46 46 46 45
31.3 39.6 2.1 50.0 64.6 45.8 87.5 14.6
0.004 0.021 NS NS 0.092 0.109 NS 0.039
n: number of patients - NS: not significant. Please cite this article as: Hubert D, et al, Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2..., J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.07.001
D. Hubert et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx Table 5 Evolution of biochemical parameters after 1 and 2 years of ivacaftor treatment in comparison to baseline. Before ivacaftor initiation
Year 1
Year 2
37 (80.4) 9 (19.6) 0
52 (96.2) 1 (1.9) 1 (1.9)
44 (91.7) 3 (6.3) 1 (2.1)
ALT (n, %) ≤ ULN 41 (85.4) 51 (94.4) NULN to 2 × ULN 6 (12.5) 2 (3.7) N2 × ULN 1 (2.1) 1 (1.9) C-reactive protein (mg/L) - mean ± SD 10.8 ± 22.2 5.1 ± 8.4a Leukocyte count (no. of cells/mm3) - 8656 ± 2720 7775 ± mean ± SD 2658b Platelet count (no. of cells/mm3) 291,297 ± 273,005 ± mean ± SD 84,010 70,570d
44 (91.7) 3 (6.3) 1 (2.1) 7.0 ± 16.9 7616 ± 2468c 273,806 ± 84,694e
AST (n, %) ≤ ULN NULN to 2 × ULN N2 × ULN
AST: aspartate aminotransferase - ALT: alanine aminotransferase - ULN: upper limit of normal - ap b 0.03; bp b 0.01; cp b 0.04; dp b 0.002; ep b 0.003.
C-reactive protein values decreased significantly only at Year 1 (Table 5). 4. Discussion This observational study reports clinical data in a real-world setting after one and two years of ivacaftor treatment on a significant proportion of CF patients with a Gly551Asp-CFTR gating mutation in France. It takes into account not only pulmonary function and nutritional status, but also bacterial colonisation and treatment burden. On average, we observed an increase in FEV1, an improved nutritional status and a decrease in sweat chloride levels, which corroborates what has been reported in clinical studies [1–3]. Additionally, we report a decrease in Pseudomonas aeruginosa and Staphylococcus aureus pulmonary colonisation as well as a decrease in treatment burden. At 8.4% (p b 0.0001) after one year of ivacaftor treatment, the mean absolute increase in FEV1 in this study was lower than that reported in the randomised phase 3 clinical trials (10.6% for patients older than 12 [1] and 10.7% in the 6– 11 year old age group [2]) but similar to that found in a retrospective study in 26 Scottish children whose FEV1 increased by 7.1% after one year of treatment [7]. In a postapproval evaluation of ivacaftor in 151 patients over the age of 6, the increase in FEV1 was 6.7% after 6 months [8]. One possible explanation for the different results between these randomised clinical trials and observational studies is that the latter included patients with severe respiratory function and a lower increase in FEV1. Another explanation suggested in the GOAL study for the reduced pulmonary improvement observed in observational studies is that the patients with the highest FEV1, N 90%, detract from the mean response [8]; high baseline spirometry is known to diminish measurable treatment effect because of a ceiling effect. In addition, it is important to note that variable or decreasing compliance over time has been reported in patients prescribed ivacaftor [9].
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We showed that the benefit of ivacaftor on lung function was sustained 2 years after treatment initiation with a mean absolute increase in FEV1 since baseline of 7.2% (p = 0.006). For the same reasons as those discussed above, this result was slightly lower than that of the phase 3 open-label PERSIST extension study, where the mean absolute change in FEV1 after 96 weeks of ivacaftor was 9.5 and 9.1% among adolescents/ adults, and 10.5 and 9% in children [3]; the benefits of ivacaftor were sustained for up to 144 weeks with a mean absolute change in FEV1 of 9.4% among adolescents/adults and 10.3% in children [3]. Patients with an FEV1 b 40% predicted represent a significant proportion of eligible patients for ivacaftor therapy but were excluded from clinical trials. Previous studies, conducted in the context of compassionate programs, reported a mean absolute increase in FEV1 of 5.2% within the first year of treatment [10], 4.2% after 3 to 9 months [11], and 5.5% at 24 weeks [12]. This is comparable to the absolute increase in FEV1 of 5% observed in our study after one year of treatment. In our patient cohort, the benefits in respiratory function were sustained after 2 years. The increase in weight and BMI observed in our population was also similar to those reported in previous studies [1–3,7,8]. Treatment with ivacaftor has been shown to improve weight and body mass index for patients with a Gly551Asp-CFTR mutation over a 3-year period [3,6]. The GOAL study showed that duodenal bicarbonate levels increased with ivacaftor to levels approaching normal, confirming that gastrointestinal pH normalisation could be part of the mechanism of improved food and nutrient absorption and subsequent weight gain [8,13]. Another likely explanation is the decrease in inflammatory and infectious conditions leading to a decrease in energy expenditure [14]. We also found that Pseudomonas aeruginosa and Staphylococcus aureus culture positivity were significantly reduced after one and two years of ivacaftor therapy. A similar observation was made in the GOAL study, which reported a lower incidence of infection with P. aeruginosa [8], where the odds of P. aeruginosa positivity in the year after ivacaftor compared with the preceding year were reduced by 35% [15]. Ivacaftor was also associated with reduced odds of mucoid P. aeruginosa and Aspergillus, but not Staphylococcus aureus or other common CF pathogens [15]. Another study in 8 CF adults who had chronic P. aeruginosa colonisation reported that ivacaftor produced a rapid decrease in sputum P. aeruginosa density, which continued in the first year of treatment. However, no subject was able to eradicate their P. aeruginosa strain and, after the first year, P. aeruginosa density rebounded [16]. Interestingly, in vitro data indicate that ivacaftor exhibits antibiotic properties, inhibiting the growth of respiratory isolates of S. aureus and Streptococcus pneumoniae, and to a lesser extent that of P. aeruginosa [17]. We did not find any change in the prevalence of exocrine pancreatic insufficiency or diabetes in patients treated with ivacaftor. However, there was a trend for decreasing HbA1c levels. An increased insulin response to oral glucose was reported in one study after one month of treatment, leading the
Please cite this article as: Hubert D, et al, Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2..., J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.07.001
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investigators to conclude that ivacaftor could play a role in delaying or preventing the development of CFRD [18]. A case-report of CFRD resolution with ivacaftor therapy in a 25-year-old male with CF has been published [19]. Although improvements in bone mass density have been reported in 7 adult patients carrying a Gly551Asp-CFTR mutation and taking ivacaftor [20], our results were not conclusive. This might partly be explained by the fact that our population was younger and had better bone mass density at baseline. Sweat chloride decreased significantly after initiation of ivacaftor, reflecting augmented CFTR function, similarly to what was reported in the phase 3 clinical trials [1–3] as well as in prospective [8] and retrospective [7] observational studies. By improving CFTR function, ivacaftor has been shown to decrease the incidence of pulmonary exacerbations [1–3]. Rowe et al. reported a decrease in hospitalisation rates between the year prior to ivacaftor initiation and the first year of treatment [8]. We did not find a decrease in the number of hospitalisations, but hospitalisation rates are low in France thanks to the common practice of home IV treatments. On the other hand, our results do demonstrate a statistically significant decrease in IV antibiotic courses for each of the two years after ivacaftor initiation in comparison to the preceding year. A decline in the number of IV antibiotic days has been reported only in severe patients during the first year of treatment [11]. A paediatric 12-month observational study showed a reduction in the use of IV and oral antibiotics after ivacaftor initiation [7]. Our results also show a decrease in oral antibiotics with ivacaftor in the second year. Our study is the first to demonstrate a reduction in maintenance treatment under ivacaftor in comparison to the previous year. Prescriptions of azithromycin decreased within the first year of treatment and those of Dornase alpha and oral supplements started to decrease in the second year, reflecting a sustained benefit of ivacaftor on pulmonary and nutritional status. The design of our study does not enable us to determine whether changes in prescriptions resulted from physician or patient initiative. Yet the differences observed between year 1 and year 2 suggest that azithromycin and DNase prescription modifications occurred after an extended period of time on ivacaftor once patient clinical symptoms improved. This raises interesting questions regarding a potential impact on the long-term benefits of ivacaftor and whether ivacaftor could lead to the safe discontinuation/reduction of other long-term therapies. Similarly, the use of bronchodilators and inhaled corticosteroids appeared to decrease in the second year. Longer observational studies with larger samples are needed to confirm this trend. The use of pancreatic enzymes was unchanged, which is consistent with the persistence of exocrine pancreatic insufficiency. The absence of reduction of inhaled antibiotics must be considered in the context of less IV antibiotic therapy and the need for maintaining antibacterial treatment. No significant side effects were noted that could be linked to ivacaftor although two subjects discontinued ivacaftor due to elevated liver enzymes and diagnosis of cirrhosis. However, after 2 years of treatment with ivacaftor, no evidence of a substantial increase in the frequency or severity of elevations in
liver function tests could be found. Ten patients out of the 55 who remained on ivacaftor by the end of the study (18%) had interrupted ivacaftor treatment for a short period. Although our results provide important information on ivacaftor effectiveness and tolerance over the long term, our study has limitations. Due to the retrospective study design, it was not possible to collect precise data on pulmonary exacerbations, as criteria for defining an exacerbation were not homogenous from one CF centre to the next. We chose to use the number of IV antibiotics, and to a lesser extent of oral antibiotic treatments, to reflect the onset of pulmonary exacerbations. Data collection for adverse events could therefore have been incomplete, leading to a possible under-estimation of adverse events. Quality of life questionnaires might have provided useful insights but could not be collected. Our study could therefore not corroborate the change in CFQR respiratory domain scores that have been demonstrated in prospectively designed clinical trials [1,3]. In conclusion, in a real-world setting ivacaftor treatment for patients with CF and at least one copy of the Gly551AspCFTR confirmed the improvements in FEV1 and weight that were reported in interventional studies. Moreover, ivacaftor was associated with a decrease in P. aeruginosa and Staphylococcus aureus colonisation, and with fewer IV antibiotic and maintenance treatment prescriptions (including azithromycin, Dornase alpha and nutritional supplements). These changes were sustained after 2 years. No safety alerts could be detected. Nevertheless, further studies are warranted on a larger number of patients, including those with other gating CFTR mutations, to improve knowledge of the long-term effectiveness and safety of ivacaftor. Acknowledgements The authors would like to thank the investigators from French CF centres: Benoît Desrues (Pontchaillou Hospital, Rennes, France), Eric Deneuville (Hôpital Sud, Rennes, France), Gilles Rault (Centre héliomarin de Perharidy, Roscoff, France), Dominique Grenet (Foch Hospital, Suresnes, France), Bertrand Delaisi and Michèle Gérardin (Robert Debré Hospital, AP-HP, Paris, France), Murielle Le Bourgeois and Isabelle Sermet-Gaudelus (Necker Hospital, AP-HP, Paris, France), Alain Haloun (Laënnec Hospital, Nantes, France), Isabelle Durieu (Hospices Civils de Lyon, Pierre-Bénite, France), Stéphanie Vrielinck (Hôpital Femme-Mère-Enfant, Bron, France), Anne Prévotat and Thierry Perez (Calmette Hospital, Lille, France), Antoine Deschildre (Jeanne de Flandre Hospital, Lille), Charlotte Giraut and Sophie Marchand (Clocheville Hospital, Tours), Anne-Cécile Henriet-Gérolt (Bretonneau Hospital, Tours), Natacha Remus (Centre Hospitalier Intercommunal de Créteil, Créteil, France), Sylvie Leroy (FHU OncoAge, Côte d'Azur University, Nice, France), Stéphanie Bui (Pellegrin Hospital, Bordeaux, France), Muriel Laurans (University Hospital Côte de Nacre, Caen, France), Jocelyne Derelle (Hôpital d'Enfants, Nancy, France), Laurence Weiss (Hautepierre Hospital, Strasbourg, France), Annlyse Fanton (Hôpital d'Enfants du Bocage, Dijon, France), Véronique
Please cite this article as: Hubert D, et al, Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2..., J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.07.001
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Storni (Bretagne Atlantique Hospital, Vannes, France), Philippe Vigneron (Bretagne Sud Hospital, Lorient, France), Jean-Louis Ginies (Angers Hospital, Angers, France). The authors would also like to thank Espérie Burnet for rereading the English version of the article. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.jcf.2017.07.001. References [1] Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365(18):1663–72. [2] Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med 2013;187(11):1219–25. [3] McKone EF, Borowitz D, Drevinek P, Griese M, Konstan MW, Wainwright C, et al, VX08-770-105 (PERSIST) Study Group. Longterm safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). Lancet Respir Med 2014;2:902–10. [4] De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros 2014;13:674–80. [5] Davies JC, Cunningham S, Harris WT, Lapey A, Regelmann WE, Sawicki GS, et al. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med 2016;4: 107–15. [6] Sawicki GS, McKone EF, Pasta DJ, Millar SJ, Wagener JS, Johnson CA, et al. Sustained benefit from ivacaftor demonstrated by combining clinical trial and cystic fibrosis patient registry data. Am J Respir Crit Care Med 2015;192(7):836–42. [7] Dryden C, Wilkinson J, Young D, Brooker RJ, Scottish Paediatric Cystic Fibrosis Managed Clinical Network (SPCFMCN). The impact of 12 months treatment with ivacaftor on Scottish paediatric patients with cystic fibrosis with the G551D mutation: a review. Arch Dis Child June 10 2016. http://dx.doi.org/10.1136/archdischild-2015-310420 [pii: archdischild-2015-310420].
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[8] Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, et al. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014;190(2):175–84. [9] Siracusa CM, Ryan J, Burns L, Wang Y, Zhang N, Clancy JP, et al. Electronic monitoring reveals highly variable adherence patterns in patients prescribed ivacaftor. J Cyst Fibros 2015;14(5):621–6. [10] Hebestreit H, Sauer-Heilborn A, Fischer R, Käding M, Mainz JG. Effects of ivacaftor on severely ill patients with cystic fibrosis carrying a G551D mutation. J Cyst Fibros 2013;12(6):599–603. [11] Barry PJ, Plant BJ, Nair A, Bicknell S, Simmonds NJ, Bell NJ, et al. Effects of ivacaftor in patients with cystic fibrosis who carry the G551D mutation and have severe lung disease. Chest 2014;146(1):152–8. [12] Taylor-Cousar J, Niknian M, Gilmartin G, Pilewski JM, for the VX11770-901 investigators. Effect of ivacaftor in patients with advanced cystic fibrosis and a G551D-CFTR mutation: safety and efficacy in an expanded access program in the United States. J Cyst Fibros 2016;15(1):116–22. [13] Borowitz D, Lubarsky B, Wilschanski M, Munck A, Gelfond D, Bodewes F, et al. Nutritional status improved in cystic fibrosis patients with the G551D mutation after treatment with ivacaftor. Dig Dis Sci 2016;61(1): 198–207. [14] Castro M, Diamanti A, Gambarara M, Bella S, Lucidi V, Papadatou B, et al. Resting energy expenditure in young patients with cystic fibrosis receiving antibiotic therapy for acute respiratory exacerbations. Clin Nutr 2002;2(2):141–4. [15] Heltshe SL, Mayer-Hamblett N, Burns JL, Khan U, Baines A, Ramsey BW, et al. Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. Clin Infect Dis 2015;60(5):703–12. [16] Hisert KB, Heltshe SL, Pope C, Jorth P, Wu X, Edwards RM, et al. Restoring CFTR function reduces airway bacteria and inflammation in people with cystic fibrosis and chronic lung infections. Am J Respir Crit Care Med 2017;195(12):1617–28. [17] Reznikov LR, Abou Alaiwa MH, Dohm CL, Gansemer MD, Diekema DJ, Stoltz DA, et al. Antibacterial properties of the CFTR potentiator ivacaftor. J Cyst Fibros 2014;13(5):515–9. [18] Bellin MD, Laguna T, Leschyshyn J, Regelmann W, Dunitz J, Billings J, et al. Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study. Pediatr Diabetes 2013;14: 417–21. [19] Hayes D, McCoy KS, Sheikh SI. Resolution of cystic fibrosis–related diabetes with ivacaftor therapy. Am J Respir Crit Care Med 2014;190(5): 590–1. [20] Sermet-Gaudelus I, Delion M, Durieu I, Jacquot J, Hubert D. Bone demineralization is improved by ivacaftor in patients with cystic fibrosis carrying the p.Gly551Asp mutation. J Cyst Fibros 2016;15(6):e67–9.
Please cite this article as: Hubert D, et al, Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2..., J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.07.001
Journal of Cystic Fibrosis xx (2017) xxx – xxx www.elsevier.com/locate/jcf
Original Article
Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2 years of treatment with ivacaftor in a real-world setting Dominique Hubert a,b,⁎, Clémence Dehillotte c , Anne Munck d , Valérie David e , Jinmi Baek f , Laurent Mely g , Stéphane Dominique h , Sophie Ramel i , Isabelle Danner Boucher j , Sylvaine Lefeuvre k , Quitterie Reynaud l , Virginie Colomb-Jung c , Prissile Bakouboula f , Lydie Lemonnier c a
h
Pulmonary Department, Adult CF Centre, Cochin Hospital, AP-HP, Paris, France b Université Paris Descartes, Sorbonne Paris Cité, Paris, France c Vaincre la Mucoviscidose, Paris, France d Pediatric CF Centre, Robert Debré Hospital, AP-HP, Paris, France e Pediatric CF Centre, Hôpital Mère-Enfant, Nantes, France f Clinical Research Unit, Cochin Hospital, AP-HP, Paris, France g CF Centre, Renée Sabran Hospital, Giens, France Pulmonary Department, Adult CF Centre, Charles Nicolle Hospital, Rouen University Hospital, Rouen, France i CF Centre, Centre héliomarin de Perharidy, Roscoff, France j Pulmonary Department, Adult CF Centre, Laennec Hospital, Nantes, France k Paediatric CF Centre, Hôpital Sud, Rennes, France l Adult CF Centre Lyon Sud, Hospices Civils de Lyon, Lyon, France Received 3 April 2017; revised 3 July 2017; accepted 3 July 2017 Available online xxxx
Abstract Background: Ivacaftor has been shown to improve lung function and body weight in patients with CF and a gating mutation. Real-world evaluation is warranted to examine its safety and effectiveness over the long term. Methods: A retrospective observational multicentre study collected clinical data in the year before and the 2 years after ivacaftor initiation in patients with CF and a Gly551Asp-CFTR mutation. Results: Fifty-seven patients were included. Mean absolute change in FEV1% predicted improved from baseline to Year 1 (8.4%; p b 0.001) and Year 2 (7.2%; p = 0.006). Statistically significant benefits were observed with increased body mass index, fewer Pseudomonas aeruginosa and Staphylococcus aureus positive cultures, and decreased IV antibiotics and maintenance treatment prescriptions (including azithromycin, Dornase alpha and nutritional supplements). No significant adverse events were reported. Conclusion: The clinical benefits of ivacaftor reported in previous clinical trials were confirmed in a real-world setting two years post-initiation, also reducing treatment burden. © 2017 Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. Keywords: Cystic fibrosis; CFTR modulators; Lumacaftor
⁎ Corresponding author at: Pulmonary Department, Adult CF Centre, Cochin Hospital, AP-HP, Paris, France. E-mail address: [email protected] (D. Hubert).
http://dx.doi.org/10.1016/j.jcf.2017.07.001 1569-1993/© 2017 Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. Please cite this article as: Hubert D, et al, Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2..., J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.07.001
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D. Hubert et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
1. Introduction Ivacaftor is an oral cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that improves chloride transport in cells expressing certain CFTR gating mutations. In clinical trials lasting up to 144 weeks, ivacaftor was shown to improve lung function, body weight, and sweat chloride in patients with cystic fibrosis (CF) and a Gly551Asp-CFTR mutation [1–3]. Ivacaftor was approved by the Food and Drug Administration and by the European Medicines Agency in 2012 for the treatment of CF patients over the age of six with a Gly551Asp-CFTR mutation. It has been available in France since April 2012 for these patients, regardless of their respiratory function level. Ivacaftor was subsequently shown to be effective in carriers of other CFTR gating mutations [4] (available in France from May 2015) and in children aged 2 to 5 with CF and a CFTR gating mutation [5] (available from February 2017). The benefits of ivacaftor reported in clinical trials were evident, and studies from the US Registry suggested that improvements in respiratory function and nutritional status were maintained after 3 years of treatment [6]. To confirm these results and to provide additional information on other aspects of the disease, such as changes in bacterial lung colonisation and treatment needs, we designed a “real-world study” in the French population. The objective of our study was to evaluate the clinical response to ivacaftor in French CF patients aged 6 or older with a Gly551Asp-CFTR mutation after 1 and 2 years of treatment in a real-world setting. 2. Methods A multicentre retrospective observational study was conducted on patients with CF and at least one Gly551Asp-CFTR mutation who had initiated treatment with ivacaftor before 1st June 2013. Ivacaftor treatment reporting in the French CF Registry began in 2013, therefore eligible patients had to be recruited through their CF Centre. Each of the 45 French CF centres were contacted and asked if they had patients who had been treated with ivacaftor before 1st June 2013; 25 confirmed they did and agreed to participate, and 57 patients were included. No information was collected about eligible patients with Gly551Asp-CFTR who were not taking ivacaftor. Demographic and clinical data were collected by a clinical research assistant from patient files for the year prior to and the year after ivacaftor was initiated. When available, clinical data collection was extended to the second year of ivacaftor treatment; this applied to the subjects for whom treatment had been initiated before 30th September 2012 as data collection stopped on 30th September 2014. All the patients who had been included in the initial phase 3 ivacaftor clinical trials were also included in this study; the date of initiation was determined after their placebo/treatment group allocation was revealed. The primary endpoint under consideration in our analysis was the absolute change in forced expiratory volume in one
second (FEV1) from baseline (last value before ivacaftor initiation) to 12 months after treatment initiation. FEV1 data was collected in litres and expressed as percentage of the predicted value according to Knudson's reference. Secondary endpoints were the absolute change from baseline to 24 months in percent predicted FEV1, and changes from baseline to 12 and 24 months after ivacaftor initiation in the following parameters: weight and BMI z score, bacteria isolated in sputum (Pseudomonas aeruginosa and Staphylococcus aureus), number (and number of days) of IV and oral antibiotic courses, number of outpatient visits and number of hospitalisations, and of concomitant treatments. Sweat chloride was measured before and after ivacaftor initiation. We also looked for a change in pancreatic insufficiency and diabetes mellitus status. When available, we collected results of bone mass density measured by dual energy X-ray absorptiometry (DEXA) at the L2–L4 lumbar spine and at the femoral neck at baseline and after at least one year of ivacaftor treatment. Other data collected included age at treatment initiation, gender, CFTR genotype, date of treatment initiation, any interruption or discontinuation of ivacaftor. All data were retrieved from the French CF Registry. Adverse events, excluding pulmonary exacerbations, were collected retrospectively from patient files. The database collected for this study was added to the French Registry after it had been completed. Safety and tolerance evaluation was based on the adverse events observed during the two-year follow-up. Clinical laboratory values (haematology, C-Reactive Protein, liver enzymes, HbA1c) were collected before ivacaftor initiation and at 12 and 24 months. The study was approved by our Institutional Review Board (file # 13.652). All subjects received written information and provided verbal informed consent; following French regulations regarding observational studies, no signed agreement was requested. This study is registered with Clinical Trials.gov., number NCT02194881. 2.1. Statistical analysis Quantitative variables are expressed as means and standard deviations. Medians and ranges are used as appropriate. Descriptive data are expressed as proportions (%) of patients for whom data were available. Year 1 and Year 2 data were compared with baseline values using paired Student's t-tests and non-parametric Wilcoxon tests for continuous data and McNemar's tests for categorical data. All analyses were performed using SAS 9.4 (SAS Institute, Cary, NC). Two-sided p-values b 0.05 were considered statistically significant. The statistical analysis is limited by multiple comparisons, which was not adjusted for. 3. Results 3.1. Subjects The study population consisted of 57 patients with CF, including 30 children and adolescents and 27 adults (47%),
Please cite this article as: Hubert D, et al, Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2..., J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.07.001
D. Hubert et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
with a mean age (± SD) of 21.5 (± 13.1) years. Their clinical characteristics at ivacaftor initiation are shown in Table 1. Six of them had previously participated in the initial phase 3 clinical trials. Nine had severe respiratory function (FEV1 b 40%). At Year 1, the study included fifty-six subjects as treatment had been discontinued in one patient. At Year 2, 48 subjects were still included; one had discontinued ivacaftor treatment and 7 patients had not reached a two-year treatment duration. 3.2. Respiratory function (Table 2) There was a statistically significant increase in FEV1 in the entire cohort, with an absolute change in FEV1 of 8.4% at Year 1 (p b 0.001) and of 7.2% at Year 2 (p = 0.006) in comparison to FEV1 prior to ivacaftor initiation. The highest response was seen in the adolescent age group. The increase was not statistically significant in 6–12 year olds at both time points or at Year 2 in adults. The 9 patients with severe respiratory function had an absolute increase in FEV1 of 5% at Year 1 and of 4.8% at Year 2 compared to baseline, but this result was not statistically significant. 3.3. Other clinical parameters There were statistically significant increases in weight and in BMI z score in the whole cohort as well as in BMI in adults at Year 1 and Year 2 (Table 3). There was no change in the mean numbers of outpatient visits and of sputum sample analyses during Year 1 compared to the year prior to ivacaftor initiation though they were lower during Year 2 (Table 3). Pulmonary bacterial colonisation with Pseudomonas aeruginosa and Staphylococcus aureus decreased after one year of treatment, and remained low after 2 years (Table 3).
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Table 2 Absolute change in per cent predicted FEV1 at Year 1 and Year 2 after ivacaftor treatment initiation in comparison to baseline. Year 1 n All subjects
56
Year 2
Mean p Value change ± SD 8.4 ± 14.3
n
Mean p Value change ± SD
0.0001 44
7.2 ± 15.5
0.006
Subjects by age distribution 6–12 years 16 7.3 ± 19.0 ≥12–18 years 14 12.5 ± 11.5 ≥18 years 26 7.0 ± 12.5
NS 0.004 0.009
11 11 22
6.1 ± 18.4 12.3 ± 6.1 5.5 ± 13.9
NS 0.053 NS
Subjects by respiratory severity FEV1 ≥ 40% pred. 49 9.1 ± 15.3 FEV1 b 40% pred. 7 5.0 ± 8.8
0.0004 38 0.126 6
7.8 ± 17.2 4.8 ± 6.8
0.017 0.069
n: number of patients - NS: not significant.
In comparison to the year prior to ivacaftor initiation, the number of IV antibiotic courses (and days) decreased significantly over the first and second years and a trend towards a decrease in the oral antibiotic intake appeared over the second year (Table 3). No change in the number of hospitalisations was observed, which was very low in all periods (Table 3). The rates of pancreatic insufficiency and of cystic fibrosis related diabetes (CFRD) remained constant. HbA1c did not change significantly during the study (6.0 ± 0.9% at baseline, 5.8 ± 0.7% at Year 1 and 5.8 ± 0.6% at Year 2). Data on bone mass density were available for 22 patients and showed no apparent change: 12 patients had lumbar spine measurement (Z-score − 0.8 before and − 0.9 after ivacaftor) and 10 patients had femoral neck measurements (Z-score − 0.9 before and − 1.0 after ivacaftor).
Table 1 Baseline patient characteristics. Population
All (n = 57)
Children (6–12 yrs) (n = 16)
Adolescents (≥ 12–18 yrs) (n = 14)
Adults (N 18 yrs) (n = 27)
17.6 (6.1–51.8)
8.2 (6.1–11.8)
14.2 (12.1–17.7)
31.3 (18.9–51.8)
Sex Male, n (%) Female, n (%) Age at diagnosis in years, median (range)
34 (59.6) 23 (40.4) 0.5 (0–37.3)
8 (50) 8 (50) 0.1 (0–0.3)
8 (57.1) 6 (42.9) 0.9 (0–15.7)
18 (66.7) 9 (33.3) 3.0 (0–37.3)
CFTR genotype, n (%) G551D/F508del Severe genotype Mild genotype Pancreatic insufficiency, n (%) Diabetes, n (%) Weight, kg (mean ± SD) FEV1,% predicted (mean ± SD) FEV1 b 40%, n (%)
34 (59.6) 48 (84.2) 9 (15.8) 47 (82.5%) 7 (12.3%) 48.2 ± 17.6 72.3 ± 26.4 9 (15.8)
12 (75) 15 (93.8) 1 (6.3) 14 (87.5) 0 25.9 ± 6.7 84.3 ± 12.7 0
8 (57.1) 13 (92.9) 1 (7.1) 11 (84.6) 0 49.5 ± 13.1 86.0 ± 24.4 1 (8.3)
14 (51.9) 20 (74.1) 7 (25.9) 22 (81.5) 7 (26.9) 61.4 ± 7.4 59.5 ± 27.2 8 (30.8)
Bacterial respiratory colonisation, n (%) Pseudomonas aeruginosa Staphylococcus aureus Sweat chloride, mmol/L (mean ± SD)
32 (58.2) 42 (75.0) 100.6 ± 29.3
4 (26.7) 13 (86.7) 111.9 ± 30.3
8 (61.5) 10 (71.4) 91.7 ± 24.5
20 (74.1) 19 (70.4) 99.0 ± 30.1
Age in years, median (range)
Please cite this article as: Hubert D, et al, Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2..., J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.07.001
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Table 3 Evolution of other clinical parameters after one and 2 years of ivacaftor treatment in comparison to baseline. Baseline
Weight (kg) BMI z-score BMI in adults (kg/m2) Number of outpatient visits/year Number of sputum sample analyses/year Pseudomonas aeruginosa Staphylococcus aureus Number of IV antibiotic courses/year Number of days of IV antibiotic courses/year Number of oral antibiotic courses/year Number of days of oral antibiotic courses/year Number of hospitalisations/year Number of days of hospitalisation/year
Year 1
Year 2
n
Mean ± SD or proportion of patients (%)
n
Mean ± SD or proportion of patients (%)
p Value
n
Mean ± SD or proportion of patients (%)
p Value
54 54 26 57 52 52 52 57 57 57 57 57 57
48.2 ± 17.6 0 ± 0.9 21.2 ± 1.5 6.0 ± 3.7 5.0 ± 2.7 58.2 75.0 0.9 ± 1.3 12.7 ± 21.0 1.8 ± 2.1 37.2 ± 58.0 0.4 ± 1.0 2.4 ± 8.0
55 55 25 56 52 52 52 56 56 56 56 56 56
52.3 ± 17.5 0.3 ± 1.0 22.1 ± 1.9 5.8 ± 2.9 4.3 ± 1.7 33.3 57.4 0.3 ± 0.9 5.6 ± 15.3 1.1 ± 1.6 23.4 ± 52.9 0.2 ± 0.7 1.2 ± 5.2
b0.0001 b0.0001 0.0004 NS NS 0.0005 0.004 0.008 0.013 0.120 0.118 NS NS
45 45 19 48 47 47 47 48 48 48 48 48 48
53.8 ± 16.9 0.4 ± 1.1 22.7 ± 2.7 4.9 ± 3.0 3.4 ± 1.9 41.3 58.7 0.3 ± 0.8 5.4 ± 14.7 1.1 ± 1.6 23.6 ± 57.7 0.3 ± 1.0 2.2 ± 7.6
b0.0001 b0.0001 0.003 0.038 0.001 0.039 0.022 0.011 0.016 0.072 0.055 NS NS
n: number of patients - NS: not significant.
3.4. CFTR function Sweat chloride levels decreased significantly with ivacaftor treatment with a mean (± SD) of 100.6 (± 29.3) mmol/L before and 40.1 (± 24.7) mmol/L after initiation (p b 0.001). 3.5. Maintenance treatment (Table 4) The number of azithromycin prescriptions decreased over the first and the second years of ivacaftor therapy. Dornase alfa prescriptions and oral supplements decreased only during the second year of ivacaftor treatment. Hypertonic saline was less frequently prescribed after ivacaftor initiation, but the result was not statistically significant as the number of patients involved was much lower. There was a trend for less frequent inhaled bronchodilators and corticosteroids in the second year of ivacaftor treatment. No change was observed for inhaled antibiotics or pancreatic enzymes. 3.6. Safety and adverse events Excluding pulmonary exacerbations, a total of 34 adverse events were reported in 21 patients. Some occurred soon after
ivacaftor initiation and disappeared within a few days: fever, rhino-pharyngitis, nausea, abdominal pain and impaired intestinal motility, headache, myalgia, fatigue and orchitis. Adverse events that lasted more than a month included abdominal pain and vomiting, rash or eczema, chest pain, atrial fibrillation, depression, arthritis, asthma, breast hypertrophy and headache. Liver abnormalities were reported in 3 patients. No deaths or lung transplantations occurred in the first 2 years of ivacaftor treatment. Ivacaftor was discontinued in two patients at 24 and 53 weeks of treatment, due to increased liver enzyme levels and diagnosis of liver cirrhosis, respectively. There were 12 interruptions of ivacaftor in 10 patients, after a mean treatment duration of 261 days (range: 7–589 days) and with a mean duration of 60 days (range: 1–220 days). These interruptions were motivated by clinical signs including hepatitis, rash, rhino-pharyngitis, abdominal pain, vomiting, headache and severe depression or were the result of poor compliance (in 3 patients). Overall, no increase in hepatic transaminase levels was observed. Red cell counts remained stable and a significant decrease in white blood cell and platelet counts was noted (Table 5). These changes are not likely clinically meaningful.
Table 4 Changes in maintenance treatment after 1 and 2 years of ivacaftor treatment in comparison to baseline. Baseline
Azithromycin Dornase alfa Hypertonic saline Inhaled antibiotics Inhaled bronchodilators Inhaled corticosteroids Pancreatic enzymes Oral supplements
Year 1
Year 2
n
Proportion of patients (%)
n
Proportion of patients (%)
p Value
n
Proportion of patients (%)
p Value
55 57 56 55 57 56 56 53
47.4 56.1 15.8 59.6 80.7 63.2 89.5 28.1
55 55 55 55 53 55 55 53
35.7 50.0 8.9 57.1 69.6 58.9 91.1 23.2
0.039 NS NS NS NS NS NS NS
46 46 46 46 46 46 46 45
31.3 39.6 2.1 50.0 64.6 45.8 87.5 14.6
0.004 0.021 NS NS 0.092 0.109 NS 0.039
n: number of patients - NS: not significant. Please cite this article as: Hubert D, et al, Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2..., J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.07.001
D. Hubert et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx Table 5 Evolution of biochemical parameters after 1 and 2 years of ivacaftor treatment in comparison to baseline. Before ivacaftor initiation
Year 1
Year 2
37 (80.4) 9 (19.6) 0
52 (96.2) 1 (1.9) 1 (1.9)
44 (91.7) 3 (6.3) 1 (2.1)
ALT (n, %) ≤ ULN 41 (85.4) 51 (94.4) NULN to 2 × ULN 6 (12.5) 2 (3.7) N2 × ULN 1 (2.1) 1 (1.9) C-reactive protein (mg/L) - mean ± SD 10.8 ± 22.2 5.1 ± 8.4a Leukocyte count (no. of cells/mm3) - 8656 ± 2720 7775 ± mean ± SD 2658b Platelet count (no. of cells/mm3) 291,297 ± 273,005 ± mean ± SD 84,010 70,570d
44 (91.7) 3 (6.3) 1 (2.1) 7.0 ± 16.9 7616 ± 2468c 273,806 ± 84,694e
AST (n, %) ≤ ULN NULN to 2 × ULN N2 × ULN
AST: aspartate aminotransferase - ALT: alanine aminotransferase - ULN: upper limit of normal - ap b 0.03; bp b 0.01; cp b 0.04; dp b 0.002; ep b 0.003.
C-reactive protein values decreased significantly only at Year 1 (Table 5). 4. Discussion This observational study reports clinical data in a real-world setting after one and two years of ivacaftor treatment on a significant proportion of CF patients with a Gly551Asp-CFTR gating mutation in France. It takes into account not only pulmonary function and nutritional status, but also bacterial colonisation and treatment burden. On average, we observed an increase in FEV1, an improved nutritional status and a decrease in sweat chloride levels, which corroborates what has been reported in clinical studies [1–3]. Additionally, we report a decrease in Pseudomonas aeruginosa and Staphylococcus aureus pulmonary colonisation as well as a decrease in treatment burden. At 8.4% (p b 0.0001) after one year of ivacaftor treatment, the mean absolute increase in FEV1 in this study was lower than that reported in the randomised phase 3 clinical trials (10.6% for patients older than 12 [1] and 10.7% in the 6– 11 year old age group [2]) but similar to that found in a retrospective study in 26 Scottish children whose FEV1 increased by 7.1% after one year of treatment [7]. In a postapproval evaluation of ivacaftor in 151 patients over the age of 6, the increase in FEV1 was 6.7% after 6 months [8]. One possible explanation for the different results between these randomised clinical trials and observational studies is that the latter included patients with severe respiratory function and a lower increase in FEV1. Another explanation suggested in the GOAL study for the reduced pulmonary improvement observed in observational studies is that the patients with the highest FEV1, N 90%, detract from the mean response [8]; high baseline spirometry is known to diminish measurable treatment effect because of a ceiling effect. In addition, it is important to note that variable or decreasing compliance over time has been reported in patients prescribed ivacaftor [9].
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We showed that the benefit of ivacaftor on lung function was sustained 2 years after treatment initiation with a mean absolute increase in FEV1 since baseline of 7.2% (p = 0.006). For the same reasons as those discussed above, this result was slightly lower than that of the phase 3 open-label PERSIST extension study, where the mean absolute change in FEV1 after 96 weeks of ivacaftor was 9.5 and 9.1% among adolescents/ adults, and 10.5 and 9% in children [3]; the benefits of ivacaftor were sustained for up to 144 weeks with a mean absolute change in FEV1 of 9.4% among adolescents/adults and 10.3% in children [3]. Patients with an FEV1 b 40% predicted represent a significant proportion of eligible patients for ivacaftor therapy but were excluded from clinical trials. Previous studies, conducted in the context of compassionate programs, reported a mean absolute increase in FEV1 of 5.2% within the first year of treatment [10], 4.2% after 3 to 9 months [11], and 5.5% at 24 weeks [12]. This is comparable to the absolute increase in FEV1 of 5% observed in our study after one year of treatment. In our patient cohort, the benefits in respiratory function were sustained after 2 years. The increase in weight and BMI observed in our population was also similar to those reported in previous studies [1–3,7,8]. Treatment with ivacaftor has been shown to improve weight and body mass index for patients with a Gly551Asp-CFTR mutation over a 3-year period [3,6]. The GOAL study showed that duodenal bicarbonate levels increased with ivacaftor to levels approaching normal, confirming that gastrointestinal pH normalisation could be part of the mechanism of improved food and nutrient absorption and subsequent weight gain [8,13]. Another likely explanation is the decrease in inflammatory and infectious conditions leading to a decrease in energy expenditure [14]. We also found that Pseudomonas aeruginosa and Staphylococcus aureus culture positivity were significantly reduced after one and two years of ivacaftor therapy. A similar observation was made in the GOAL study, which reported a lower incidence of infection with P. aeruginosa [8], where the odds of P. aeruginosa positivity in the year after ivacaftor compared with the preceding year were reduced by 35% [15]. Ivacaftor was also associated with reduced odds of mucoid P. aeruginosa and Aspergillus, but not Staphylococcus aureus or other common CF pathogens [15]. Another study in 8 CF adults who had chronic P. aeruginosa colonisation reported that ivacaftor produced a rapid decrease in sputum P. aeruginosa density, which continued in the first year of treatment. However, no subject was able to eradicate their P. aeruginosa strain and, after the first year, P. aeruginosa density rebounded [16]. Interestingly, in vitro data indicate that ivacaftor exhibits antibiotic properties, inhibiting the growth of respiratory isolates of S. aureus and Streptococcus pneumoniae, and to a lesser extent that of P. aeruginosa [17]. We did not find any change in the prevalence of exocrine pancreatic insufficiency or diabetes in patients treated with ivacaftor. However, there was a trend for decreasing HbA1c levels. An increased insulin response to oral glucose was reported in one study after one month of treatment, leading the
Please cite this article as: Hubert D, et al, Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2..., J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.07.001
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D. Hubert et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
investigators to conclude that ivacaftor could play a role in delaying or preventing the development of CFRD [18]. A case-report of CFRD resolution with ivacaftor therapy in a 25-year-old male with CF has been published [19]. Although improvements in bone mass density have been reported in 7 adult patients carrying a Gly551Asp-CFTR mutation and taking ivacaftor [20], our results were not conclusive. This might partly be explained by the fact that our population was younger and had better bone mass density at baseline. Sweat chloride decreased significantly after initiation of ivacaftor, reflecting augmented CFTR function, similarly to what was reported in the phase 3 clinical trials [1–3] as well as in prospective [8] and retrospective [7] observational studies. By improving CFTR function, ivacaftor has been shown to decrease the incidence of pulmonary exacerbations [1–3]. Rowe et al. reported a decrease in hospitalisation rates between the year prior to ivacaftor initiation and the first year of treatment [8]. We did not find a decrease in the number of hospitalisations, but hospitalisation rates are low in France thanks to the common practice of home IV treatments. On the other hand, our results do demonstrate a statistically significant decrease in IV antibiotic courses for each of the two years after ivacaftor initiation in comparison to the preceding year. A decline in the number of IV antibiotic days has been reported only in severe patients during the first year of treatment [11]. A paediatric 12-month observational study showed a reduction in the use of IV and oral antibiotics after ivacaftor initiation [7]. Our results also show a decrease in oral antibiotics with ivacaftor in the second year. Our study is the first to demonstrate a reduction in maintenance treatment under ivacaftor in comparison to the previous year. Prescriptions of azithromycin decreased within the first year of treatment and those of Dornase alpha and oral supplements started to decrease in the second year, reflecting a sustained benefit of ivacaftor on pulmonary and nutritional status. The design of our study does not enable us to determine whether changes in prescriptions resulted from physician or patient initiative. Yet the differences observed between year 1 and year 2 suggest that azithromycin and DNase prescription modifications occurred after an extended period of time on ivacaftor once patient clinical symptoms improved. This raises interesting questions regarding a potential impact on the long-term benefits of ivacaftor and whether ivacaftor could lead to the safe discontinuation/reduction of other long-term therapies. Similarly, the use of bronchodilators and inhaled corticosteroids appeared to decrease in the second year. Longer observational studies with larger samples are needed to confirm this trend. The use of pancreatic enzymes was unchanged, which is consistent with the persistence of exocrine pancreatic insufficiency. The absence of reduction of inhaled antibiotics must be considered in the context of less IV antibiotic therapy and the need for maintaining antibacterial treatment. No significant side effects were noted that could be linked to ivacaftor although two subjects discontinued ivacaftor due to elevated liver enzymes and diagnosis of cirrhosis. However, after 2 years of treatment with ivacaftor, no evidence of a substantial increase in the frequency or severity of elevations in
liver function tests could be found. Ten patients out of the 55 who remained on ivacaftor by the end of the study (18%) had interrupted ivacaftor treatment for a short period. Although our results provide important information on ivacaftor effectiveness and tolerance over the long term, our study has limitations. Due to the retrospective study design, it was not possible to collect precise data on pulmonary exacerbations, as criteria for defining an exacerbation were not homogenous from one CF centre to the next. We chose to use the number of IV antibiotics, and to a lesser extent of oral antibiotic treatments, to reflect the onset of pulmonary exacerbations. Data collection for adverse events could therefore have been incomplete, leading to a possible under-estimation of adverse events. Quality of life questionnaires might have provided useful insights but could not be collected. Our study could therefore not corroborate the change in CFQR respiratory domain scores that have been demonstrated in prospectively designed clinical trials [1,3]. In conclusion, in a real-world setting ivacaftor treatment for patients with CF and at least one copy of the Gly551AspCFTR confirmed the improvements in FEV1 and weight that were reported in interventional studies. Moreover, ivacaftor was associated with a decrease in P. aeruginosa and Staphylococcus aureus colonisation, and with fewer IV antibiotic and maintenance treatment prescriptions (including azithromycin, Dornase alpha and nutritional supplements). These changes were sustained after 2 years. No safety alerts could be detected. Nevertheless, further studies are warranted on a larger number of patients, including those with other gating CFTR mutations, to improve knowledge of the long-term effectiveness and safety of ivacaftor. Acknowledgements The authors would like to thank the investigators from French CF centres: Benoît Desrues (Pontchaillou Hospital, Rennes, France), Eric Deneuville (Hôpital Sud, Rennes, France), Gilles Rault (Centre héliomarin de Perharidy, Roscoff, France), Dominique Grenet (Foch Hospital, Suresnes, France), Bertrand Delaisi and Michèle Gérardin (Robert Debré Hospital, AP-HP, Paris, France), Murielle Le Bourgeois and Isabelle Sermet-Gaudelus (Necker Hospital, AP-HP, Paris, France), Alain Haloun (Laënnec Hospital, Nantes, France), Isabelle Durieu (Hospices Civils de Lyon, Pierre-Bénite, France), Stéphanie Vrielinck (Hôpital Femme-Mère-Enfant, Bron, France), Anne Prévotat and Thierry Perez (Calmette Hospital, Lille, France), Antoine Deschildre (Jeanne de Flandre Hospital, Lille), Charlotte Giraut and Sophie Marchand (Clocheville Hospital, Tours), Anne-Cécile Henriet-Gérolt (Bretonneau Hospital, Tours), Natacha Remus (Centre Hospitalier Intercommunal de Créteil, Créteil, France), Sylvie Leroy (FHU OncoAge, Côte d'Azur University, Nice, France), Stéphanie Bui (Pellegrin Hospital, Bordeaux, France), Muriel Laurans (University Hospital Côte de Nacre, Caen, France), Jocelyne Derelle (Hôpital d'Enfants, Nancy, France), Laurence Weiss (Hautepierre Hospital, Strasbourg, France), Annlyse Fanton (Hôpital d'Enfants du Bocage, Dijon, France), Véronique
Please cite this article as: Hubert D, et al, Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2..., J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.07.001
D. Hubert et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
Storni (Bretagne Atlantique Hospital, Vannes, France), Philippe Vigneron (Bretagne Sud Hospital, Lorient, France), Jean-Louis Ginies (Angers Hospital, Angers, France). The authors would also like to thank Espérie Burnet for rereading the English version of the article. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.jcf.2017.07.001. References [1] Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365(18):1663–72. [2] Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med 2013;187(11):1219–25. [3] McKone EF, Borowitz D, Drevinek P, Griese M, Konstan MW, Wainwright C, et al, VX08-770-105 (PERSIST) Study Group. Longterm safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). Lancet Respir Med 2014;2:902–10. [4] De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros 2014;13:674–80. [5] Davies JC, Cunningham S, Harris WT, Lapey A, Regelmann WE, Sawicki GS, et al. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med 2016;4: 107–15. [6] Sawicki GS, McKone EF, Pasta DJ, Millar SJ, Wagener JS, Johnson CA, et al. Sustained benefit from ivacaftor demonstrated by combining clinical trial and cystic fibrosis patient registry data. Am J Respir Crit Care Med 2015;192(7):836–42. [7] Dryden C, Wilkinson J, Young D, Brooker RJ, Scottish Paediatric Cystic Fibrosis Managed Clinical Network (SPCFMCN). The impact of 12 months treatment with ivacaftor on Scottish paediatric patients with cystic fibrosis with the G551D mutation: a review. Arch Dis Child June 10 2016. http://dx.doi.org/10.1136/archdischild-2015-310420 [pii: archdischild-2015-310420].
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[8] Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, et al. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014;190(2):175–84. [9] Siracusa CM, Ryan J, Burns L, Wang Y, Zhang N, Clancy JP, et al. Electronic monitoring reveals highly variable adherence patterns in patients prescribed ivacaftor. J Cyst Fibros 2015;14(5):621–6. [10] Hebestreit H, Sauer-Heilborn A, Fischer R, Käding M, Mainz JG. Effects of ivacaftor on severely ill patients with cystic fibrosis carrying a G551D mutation. J Cyst Fibros 2013;12(6):599–603. [11] Barry PJ, Plant BJ, Nair A, Bicknell S, Simmonds NJ, Bell NJ, et al. Effects of ivacaftor in patients with cystic fibrosis who carry the G551D mutation and have severe lung disease. Chest 2014;146(1):152–8. [12] Taylor-Cousar J, Niknian M, Gilmartin G, Pilewski JM, for the VX11770-901 investigators. Effect of ivacaftor in patients with advanced cystic fibrosis and a G551D-CFTR mutation: safety and efficacy in an expanded access program in the United States. J Cyst Fibros 2016;15(1):116–22. [13] Borowitz D, Lubarsky B, Wilschanski M, Munck A, Gelfond D, Bodewes F, et al. Nutritional status improved in cystic fibrosis patients with the G551D mutation after treatment with ivacaftor. Dig Dis Sci 2016;61(1): 198–207. [14] Castro M, Diamanti A, Gambarara M, Bella S, Lucidi V, Papadatou B, et al. Resting energy expenditure in young patients with cystic fibrosis receiving antibiotic therapy for acute respiratory exacerbations. Clin Nutr 2002;2(2):141–4. [15] Heltshe SL, Mayer-Hamblett N, Burns JL, Khan U, Baines A, Ramsey BW, et al. Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. Clin Infect Dis 2015;60(5):703–12. [16] Hisert KB, Heltshe SL, Pope C, Jorth P, Wu X, Edwards RM, et al. Restoring CFTR function reduces airway bacteria and inflammation in people with cystic fibrosis and chronic lung infections. Am J Respir Crit Care Med 2017;195(12):1617–28. [17] Reznikov LR, Abou Alaiwa MH, Dohm CL, Gansemer MD, Diekema DJ, Stoltz DA, et al. Antibacterial properties of the CFTR potentiator ivacaftor. J Cyst Fibros 2014;13(5):515–9. [18] Bellin MD, Laguna T, Leschyshyn J, Regelmann W, Dunitz J, Billings J, et al. Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study. Pediatr Diabetes 2013;14: 417–21. [19] Hayes D, McCoy KS, Sheikh SI. Resolution of cystic fibrosis–related diabetes with ivacaftor therapy. Am J Respir Crit Care Med 2014;190(5): 590–1. [20] Sermet-Gaudelus I, Delion M, Durieu I, Jacquot J, Hubert D. Bone demineralization is improved by ivacaftor in patients with cystic fibrosis carrying the p.Gly551Asp mutation. J Cyst Fibros 2016;15(6):e67–9.
Please cite this article as: Hubert D, et al, Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2..., J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.07.001